期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 287, 期 53, 页码 44301-44319出版社
ELSEVIER
DOI: 10.1074/jbc.M112.413161
关键词
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资金
- National Institutes of Health [R01 MH084894, R01 NS37731, P01 DA12923]
- Dainippon Sumi-tomo Pharma
- National Alliance for Research on Schizophrenia and Depression
- Mortimer D. Sackler Foundation
- Ministerio de Ciencia e Innovacion Grant [SAF2009-084609]
- Basque Government [IT-199-07]
- Consejo Superior de Investigaciones Cientificas Grants [PA1003176, 200980I110]
- Medical Research Council United Kingdom [G0900050]
- University of the Basque Country, Spain
- Fundacion Alicia Koplowitz, Spain
- Consejo Superior de Investigaciones Cientificas, Spain
- MRC [G0900050] Funding Source: UKRI
- Medical Research Council [G0900050] Funding Source: researchfish
Serotonin and glutamate G protein-coupled receptor (GPCR) neurotransmission affects cognition and perception in humans and rodents. GPCRs are capable of forming heteromeric complexes that differentially alter cell signaling, but the role of this structural arrangement in modulating behavior remains unknown. Here, we identified three residues located at the intracellular end of transmembrane domain four that are necessary for the metabotropic glutamate 2 (mGlu2) receptor to be assembled as a GPCR heteromer with the serotonin 5-hydroxytryptamine 2A (5-HT2A) receptor in the mouse frontal cortex. Substitution of these residues (Ala-677(4.40), Ala-681(4.44), and Ala-685(4.48)) leads to absence of 5-HT2A.mGlu2 receptor complex formation, an effect that is associated with a decrease in their heteromeric ligand binding interaction. Disruption of heteromeric expression with mGlu2 attenuates the psychosis-like effects induced in mice by hallucinogenic 5-HT2A agonists. Furthermore, the ligand binding interaction between the components of the 5-HT2A.mGlu2 receptor heterocomplex is up-regulated in the frontal cortex of schizophrenic subjects as compared with controls. Together, these findings provide structural evidence for the unique behavioral function of a GPCR heteromer.
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